Better Outcomes Seen with Prasugrel vs High-Dose Clopidogrel in Select ACS Patients

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Prasugrel is substantially more effective than high-dose clopidogrel in treating patients with high on-treatment platelet reactivity who have acute coronary syndromes (ACS) and are undergoing percutaneous coronary intervention (PCI), according to a registry study published online January 29, 2014, ahead of print in the Journal of the American College of Cardiology.

Researchers led by Dániel Aradi, MD, PhD, of Heart Center Balatonfüred (Balatonfüred, Hungary), monitored platelet function using the Multiplate analyzer (Diapharma, West Chester, OH) in 741 consecutive high-risk ACS patients who underwent urgent PCI from September 2011 to August 2012. High platelet reactivity was defined as values greater than 46 U.

Patients without high platelet reactivity (n = 522) received a standard 75-mg dose of clopidogrel after a 600-mg loading dose. Of the roughly one-third (n = 219) of patients who were deemed to have high platelet reactivity, 58% (n = 128) received high-dose clopidogrel while the remainder (n = 91) were switched to prasugrel (60-mg loading dose followed by 10-mg maintenance dose). High-dose clopidogrel consisted of additional 600-mg loading doses up to 4 times based on daily platelet function testing to bring platelet reactivity levels into the normal range.

Prasugrel Seems the Better Option

After PCI, both prasugrel and high-dose clopidogrel reduced levels of platelet reactivity in the high reactivity patients from baseline (P < 0.0001 for both). However, prasugrel treatment resulted in more potent platelet inhibition compared with the repeated clopidogrel boluses at discharge (P < 0.0001).

In the maintenance phase, the 10-mg dose of prasugrel was associated with an increase in platelet reactivity (P < 0.0001), but 86% of patients on this therapy remained below the threshold of high platelet reactivity. On the contrary, clopidogrel treatment resulted in a rebound of reactivity during the chronic phase (P < 0.0001), with 51% of patients returning to high platelet reactivity status.

At 1 year, the risk of the primary composite endpoint (all-cause mortality, stent thrombosis, non-fatal MI, and stroke) showed a 1.7-fold increase among high platelet reactivity patients compared with those in the normal range (HR 1.67; 95% CI 1.11-2.51; P = 0.015). Overall, all-cause mortality at 1 year was 8.1%.

Compared with patients showing normal platelet reactivity, high reactivity patients given high-dose clopidogrel had higher risks for thrombotic events and bleeding (table 1).

Table 1. Clinical Outcomes at 1 Year

Abbreviation: HPR, high platelet reactivity.

In contrast, patients with high platelet reactivity who were switched to prasugrel had similar rates of thrombotic complications compared with the normal-reactivity group, with no difference in the primary endpoint (HR 0.90; 95% CI 0.44-1.81; P = 0.76) or any of its components.

After adjustment for baseline characteristics, high-dose clopidogrel still showed a 2.5-fold increase in the risk of the primary composite outcome compared with prasugrel (HR 2.53; 95% CI 1.08-5.93; P < 0.03). Additionally, multivariate analysis found high-dose clopidogrel treatment to be an independent predictor of the primary endpoint in high platelet reactivity patients (HR 1.90; 95% CI 1.17-3.08; P = 0.01).

High-dose Clopidogrel ‘Insufficient’

“High-dose clopidogrel seems to have insufficient clinical effect to overcome the higher risk of events in ACS patients with HPR,” Dr. Aradi and colleagues write. “Therefore, our registry is important to suggest that switching patients to prasugrel might decrease the risk of thrombotic events to a level similar to those without [high platelet reactivity].”

Moreover, they say the results suggest that potent antiplatelet agents like prasugrel have more complex interactions with high platelet reactivity than clopidogrel in terms of major bleeding and stent thrombosis, as high-dose clopidogrel treatment was associated with higher rates of both of these outcomes.

The authors acknowledge that the lower bleeding rates with prasugrel “might be somewhat surprising in light of the results of the TRITON trial; however, we administered prasugrel selectively to patients with [high platelet reactivity] instead of a general population analyzed in the cited trial.” As such, they add, “the results should not confute the higher risk for bleeding with prasugrel in a general ACS population, but might suggest that selected patients (such as those with [high platelet reactivity] on clopidogrel) might tolerate more potent P2Y12-inhibition without an excess risk for bleeding.”

They call for further research and randomized studies, but warn against using dose escalation of clopidogrel going forward.

Study Details

In general, the cohort comprised a very high-risk, all-comers cohort of ACS patients with 85% AMI, 48% STEMI, and 4.5% cardiogenic shock. Patients with high platelet reactivity were younger and had higher frequency of diabetes, STEMI, and more complex coronary disease reflected by a longer total stent length implanted. In contrast, patients with high platelet reactivity treated with prasugrel or high-dose clopidogrel had comparable baseline characteristics except for higher use of statins and beta-blockers in the prasugrel group.

Source:

Aradi D, Tornyos A, Pintér T, et al. Optimizing P2Y12-receptor inhibition in acute coronary syndrome patients based on platelet function testing: Impact of prasugrel and high-dose clopidogrel. J Am Coll Cardiol. 2014;Epub ahead of print.

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